Novel Role of BCL-2 in the Regulation of Apoptosis Mediated by Remodeling and Turnover of Extracellular Matrix

摘要

Bcl-2 is a potent inhibitor of apoptosis induced by a variety of insults. Bcl-2 is highly expressed in breast cancer and its expression is related to chemotherapy and radiation therapy resistance. Recent studies suggest that ECM plays a crucial role in apoptosis regulation in breast epithelial cells. In this report, we investigated whether bcl-2 inhibition of apoptosis involves regulation of ECM molecules such as MMPs and TIMPs. We reported that bcl-2 overexpression upregulates TIMP-1 and downregulates MMP-9 in breast epithelial cell lines (MCFlOA, MCFlOATG3B and MCF-7), while it has no effect on TIMP-2 expression. We demonstrated that TIMP-1 inhibits cell death induced by hydrogen peroxide, Adriamycin. In addition, TIMP-1 overexpression inhibits apoptosis following the loss of cell adhesion (anoikis) in MCFlOA cells suggesting that the anti- apoptotic activity of TIMP-1 does not depend on its ability to stabilize cell-matrix interactions. We also showed that TIMP-1 overexpression is associated with a constitutive activation of the focal adhesion kinase, a signaling molecule known to be critical for the cell survival pathway.